Marinozzi Maria Chiara, Roumenina Lubka T, Chauvet Sophie, Hertig Alexandre, Bertrand Dominique, Olagne Jérome, Frimat Marie, Ulinski Tim, Deschênes Georges, Burtey Stephane, Delahousse Michel, Moulin Bruno, Legendre Christophe, Frémeaux-Bacchi Véronique, Le Quintrec Moglie
Team Complement and Diseases Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1138, Paris, France.
Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
J Am Soc Nephrol. 2017 May;28(5):1603-1613. doi: 10.1681/ASN.2016030343. Epub 2017 Jan 17.
In C3 glomerulopathy (C3G), the alternative pathway of complement is frequently overactivated by autoantibodies that stabilize the C3 convertase C3bBb. Anti-C3b and anti-factor B (anti-FB) IgG have been reported in three patients with C3G. We screened a cohort of 141 patients with C3G and Ig-associated membranoproliferative GN (Ig-MPGN) for anti-FB and anti-C3b autoantibodies using ELISA. We identified seven patients with anti-FB IgG, three patients with anti-C3b IgG, and five patients with anti-FB and anti-C3b IgG. Of these 15 patients, ten were diagnosed with Ig-MPGN. Among those patients with available data, 92% had a nephrotic syndrome, 64% had AKI, and 67% had a documented infection. Patients negative for anti-C3b and anti-FB IgG had much lower rates of infection (17 [25%] patients with C3G and one [10%] patient with Ig-MPGN). After 48 months, four of 15 (26%) positive patients had developed ESRD or died. All 15 patients had high plasma Bb levels, six (40%) patients had low levels of C3, and nine (60%) patients had high levels of soluble C5b9. , IgG purified from patients with anti-FB Abs selectively enhanced C3 convertase activity; IgG from patients with anti-C3b/anti-FB Abs enhanced C3 and C5 cleavage. IgG from patients with anti-C3b Abs stabilized C3bBb and perturbed C3b binding to complement receptor 1 but did not perturb binding to factor H. In conclusion, the prevalence of anti-C3b/anti-FB Abs and alternative pathway activation is similar in Ig-MPGN and C3G, suggesting similar pathogenic mechanisms. Identification of the underlying defect in Ig-MPGN could lead to improved treatment.
在C3肾小球病（C3G）中，补体旁路常被使C3转化酶C3bBb稳定的自身抗体过度激活。在3例C3G患者中报告了抗C3b和抗B因子（抗FB）IgG。我们使用酶联免疫吸附测定法（ELISA）在141例C3G和IgA相关膜增生性肾小球肾炎（Ig-MPGN）患者队列中筛查抗FB和抗C3b自身抗体。我们鉴定出7例抗FB IgG患者、3例抗C3b IgG患者以及5例抗FB和抗C3b IgG患者。在这15例患者中，10例被诊断为Ig-MPGN。在有可用数据的患者中，92%患有肾病综合征，64%患有急性肾损伤（AKI），67%有记录在案的感染。抗C3b和抗FB IgG阴性的患者感染率低得多（17例[25%]C3G患者和1例[10%]Ig-MPGN患者）。48个月后，15例阳性患者中有4例（26%）发展为终末期肾病（ESRD）或死亡。所有15例患者血浆Bb水平均高，6例（40%）患者C3水平低，9例（60%）患者可溶性C5b9水平高。从抗FB抗体患者中纯化的IgG选择性增强C3转化酶活性；来自抗C3b/抗FB抗体患者的IgG增强C3和C5裂解。来自抗C3b抗体患者的IgG使C3bBb稳定并干扰C3b与补体受体1的结合，但不干扰与因子H的结合。总之，抗C3b/抗FB抗体的患病率和补体旁路激活在Ig-MPGN和C3G中相似，提示致病机制相似。确定Ig-MPGN中的潜在缺陷可能会改善治疗。
